The iron-storage protein, ferritin, and its iron-free apoprotein, apoferritin, are pivotal components of the mechanisms leading to normal iron homeostasis. A causal relationship might be postulated between the known heterogeneity in apoferritin and the functional variations in iron physiology and storage that are peculiar to different types of tissues and to certain disease states. Despite the variety of genetically determined isomeric apoferritins that have been defined by electrophoretic, immunological, and chemical means, including those found in normal vs. cancer tissues, the direct consequences of these changes in primary protein structure remain unknown. This research program investigates the differences in macromolecular form and function between the isomeric ferritins from normal and neoplastic tissues. Specific goals of the proposed program will be the acquisition of new knowledge answering the following fundamental questions: (1) Is the atomic structure of the stored mineralized iron different in the isoferritins from normal vs. neoplastic tissues? (2) Is the quaternary structure of tumor-specific apoferritin different from that of normal apoferritin? (3) Do the neoplastic isomers have different functional properties than their normal homologs? The first two topics will be studied by high resolution electron microscopy and diffraction of isolated purified samples; for the third question, biochemical measurements and manipulations of chemically purified populations of isoapoferritins, in conjunction with the ultrastructural examination of individual members in these same populations, will be used to assay such parameters as iron uptake, crystallite nucleation and growth, and iron release.